Intralesional treatment versus wide resection for central chondrosarcoma grade I in the long bones

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of intralesional treatment by curettage compared to wide resection for central chondrosarcoma grade I in long bones.


Description of the condition

Chondrosarcomas (CS) are the most common primary malignant bone tumours after osteosarcoma (Bauer 1995; Eriksson 1980; Healey 1986; Rosenthal 1984). CS are a heterogeneous group of bone malignancies that all arise from cartilaginous origin (Fletcher 2002), and constitute 20 to 27% of all primary bone tumours (Murphey 2003). Reported overall incidence is 1:200,000 to 500,000, with male and female more or less equally affected (ESMO 2012; Giuffrida 2009). Peak incidence is between the 3th and 7th decade of life (ESMO 2012; Jundt 2008). CS vary from low grade, relatively benign to high grade or dedifferentiated tumours with very poor survival. Conventional CS can originate outside the bone (periosteal or peripheral CS) or within the bone (central CS) and the latter accounts for 75% of all tumours. The outcome is predominately determined by histological grading, ranging from I to III, with higher grade tumours showing worse prognosis. Central grade I CS tumours tend to grow slowly and rarely metastasise, resulting in an 83% to 89% 10-year survival rate (Bjornsson 1998; Evans 1977; Fiorenza 2002). Microscopically, they have a matrix rich of hyaline cartilage (Gelderblom 2008). Most important clinical symptom is persistent (night) pain, although CS can be asymptomatic. Treatment of grade I CS is primarily surgery, since these tumours are generally resistant to radiation or systemic therapy (Eriksson 1980; Lee 1999).

In clinical practice, the treating physician is presented with a diagnostic dilemma. In a substantial number of cases, it is difficult to differentiate central grade I CS from its benign equivalent, enchondroma, or higher grade tumours (Eefting 2009; Geirnaerdt 1997; Mirra 1985; Randall 2005). Enchondroma can be treated conservatively (wait-and-see) or treated with curettage. Transformation towards malignancy in solitary enchondromas is extremely rare. Alternatively, intermediate- and high-grade CS have a 53 to 64% and a 29 to 38% 10-year survival rate, respectively, and show a higher number of local recurrence and distant metastases (Bjornsson 1998; Fiorenza 2002; Giuffrida 2009). They are treated with en bloc resection with reconstruction (prosthesis) or amputation, which hampers joint and limb function. Historically, orthopaedic surgeons tended to treat grade I CS similar as higher grade tumours. More recently, there is a tendency to perform intralesional surgery in grade I CS by curettage, preferably with local adjuvant therapy (Donati 2010; Leerapun 2007; Schreuder 1998; van der Geest 2008; Veth 2005). Grade I CS tumours located in the pelvis and axial skeleton are more aggressive and require other treatment strategies (Gelderblom 2008). Therefore, only treatment of tumours in the long bones will be described in this review.

Description of the intervention

Intralesional surgery in CS is carried out by curettage. During this procedure, the tumour is reached through a cortical window and resected using a curette. After curettage, local adjuvant therapy can be applied, either by phenolization or cryotherapy (see How the intervention might work). In a large number of cases, bone cement is used as an additional adjuvant. Once the cavity is filled, the cortical window is placed back and fixated followed by routine wound closure. In some cases, prophylactic hardware is needed to prevent fracturing. Depending on the site of the tumour, patients are prohibited from weight bearing 6 to 12 weeks after surgery. Curettage is indicated if the joint is not affected and if the tumour does not grow outside the bone. The most serious complications after curettage are fracture of the treated site and infection.

How the intervention might work

Curettage removes the malignant tumour cells. However, as the exact tumour margins are unknown during surgery, local adjuvant therapy is often performed. Phenol has a proven cytotoxic effect on CS cells and is used with the intention to kill tumour cells that can not be reached with the curette. Cryotherapy is also used, whereby liquid nitrogen is sprayed or poured into the bone cavity. It is thought that local freezing extends the surgical margins. In some centres, the bone cavity is filled with polymethyl methacrylate. Heat released due to the exothermic reaction of polymethyl methacrylate during hardening has an additional tumour cytotoxic effect. Given the relatively mild nature of grade I CS, we hypothesise that these measures are sufficient to cure patients. The major benefit of curettage compared to wide resection is that it is joint and limb sparing, thereby improving functional outcome. Although patients might be temporarily disabled due to decreased weight bearing after curettage, long-term functionality can be restored.

Why it is important to do this review

CS has an overall incidence rate that is relatively low compared to other types of cancer. To our knowledge, there are no prospective, randomised controlled trials (RCTs), given the low number of patients affected. In the literature, only small, retrospective case series have been published, in which intralesional treatment has been compared to wide resection (Aarons 2009; Bauer 1995; Donati 2010; Etchebehere 2005; Leerapun 2007; Schreuder 1998; van der Geest 2008). This type of study is often subject to bias and the numbers are often too small for meaningful statistical analysis. A systematic review is necessary to search for and summarise the available evidence. Hickey 2011 was a meta-analysis on this specific topic and it showed that intralesional therapy is not necessarily inferior to wide resection. In the meantime, several studies have been published, which justifies an updated overview. This review will be important, since intralesional treatment has great functional benefits compared to resection. Therefore, if the intralesional treatment is equally beneficial oncologically, it will be beneficial to perform curettage instead of wide resection. 


To assess the effects of intralesional treatment by curettage compared to wide resection for central chondrosarcoma grade I in long bones.


Criteria for considering studies for this review

Types of studies

We will include all RCTs comparing oncologic outcome of intralesional treatment of chondrosarcoma grade I to wide resection in the long bones. If studies include other types of CS, we will include those studies and retrieve data related to central grade I CS only. Generated data will be added to the larger data set.

If we do not identify any RCTs, we will include non-randomised studies with concurrent comparison groups:

  • quasi-randomised studies, non-randomised studies, prospective and retrospective cohort studies, case control studies;

  • we will also include case series of 20 or more patients;

  • case series of fewer than 20 patients will be excluded.

In order to minimise selection bias, we will only include studies that used statistical adjustment for baseline case mix using multivariable analyses (e.g. disease severity, age, co-morbidity, tumour grade).

Types of participants

We will include all patients with central grade I CS grade I in the long bones. There will be no age restrictions, although it is known that CS in childhood is very rare.

Types of interventions

We will compare intralesional treatment (curettage) with adjuvant (phenol and ethanol, cryosurgery, bone cement or both) to wide resection, including amputation.

Types of outcome measures

Primary outcomes

Primary outcome will be progression-free survival within a minimum follow-up duration of two years after primary surgery.

Secondary outcomes

We will consider the following secondary outcomes:

  • occurrence of upgrading of tumour (if available);

  • functional outcome based on musculoskeletal tumour society (MSTS) score (if available). The MSTS score is a well accepted and most commonly used score to determine function after surgery for bone tumours (Enneking 1993). It includes six categories (pain, function, emotional acceptance, use of supports, walking ability and gait), with numerical values from 0 to 5 points;

  • occurrence of the following adverse events (if available): fracture, infection, re-operation (due to other reason than progression of disease) or thromboembolic events. Grading of adverse events is outside the scope of this review.

Search methods for identification of studies

Electronic searches

We will search the following databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL);



The MEDLINE search strategy is presented in Appendix 1.

For databases other than MEDLINE, we will adapt the search strategy accordingly.

We will not apply language restrictions.

Searching other resources

We will extend our search to the reference lists of relevant articles and review articles as well as authors to replenish missing information. Related articles suggested by PubMed will also be scanned. In addition, we will search for ongoing trials by scanning online trial registries, such as Current Controlled Trials ( and search for oral and poster abstracts presented in appropriate meetings.

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management database and remove duplicates. Two authors (EFD, PCJ) will examine the remaining references independently. We will exclude those studies which clearly do not meet the inclusion criteria. In addition, we will obtain copies of the full text of potentially relevant references. Two authors (EFD, PCJ) will independently assess the eligibility of retrieved publications. Disagreements will be resolved by discussion between the two authors and if necessary by a third author (MS). Reasons for exclusion will be documented.  

Data extraction and management

For included studies, we will extract the following data.

  • Author, year of publication and journal citation (including language).

  • Country.

  • Setting.

  • Inclusion and exclusion criteria.

  • Study design and methodology.

  • Study population:

    • total number enrolled;

    • patient characteristics;

    • age.

  • Intervention details:

    • definition/details.

  • Comparison:

    • definition/details.

  • Risk of bias in study (see below).

  • Duration of follow-up.

  • Outcomes:

    • for each outcome, we will extract the outcome definition and unit of measurement (if relevant). For adjusted estimates, we will record variables adjusted for in analyses.

  • Results:

    • we will extract the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants (if applicable).

We will extract the following information.

  • For time to event data (survival and disease progression), we will extract the log of the hazard ratio (log(HR)) and its standard error from trial reports. If these are not reported, we will attempt to estimate the log (HR) and its standard error using the methods of Parmar 1998

  • For dichotomous outcomes we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate an odds ratio.

  • For continuous outcomes, we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference between treatment arms and its standard error.

  • If reported, we will extract both unadjusted and adjusted statistics.

Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which participants will be analysed in groups to which they were assigned.

We will note the time points at which outcomes were collected and reported.

We will extract data independently by two authors (EFD, PCJ) onto a data abstraction form specially designed for the review. We will resolve differences between authors by discussion or by appeal to a third author (MS) if necessary.

Assessment of risk of bias in included studies

We will assess the risk of bias in included studies using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). This will include assessment of:

  1. selection bias (random sequence generation and allocation concealment);

  2. detection bias (blinding of outcome assessment);

  3. attrition bias (incomplete outcome data);

  4. reporting bias (selective reporting of outcomes);

  5. other possible sources of bias.

Two authors (EFD, PCJ) will apply the risk of bias tool independently and differences resolved by discussion or by appeal to a third author (MS). We will summarise results in both a risk of bias graph and a risk of bias summary. We will interpret results of meta-analyses in light of the findings with respect to risk of bias.

Measures of treatment effect

We will use the following measures of the effect of treatment.

  • For time to event data, we will use the hazard ratio (HR), if possible.

  • For dichotomous outcomes, we will use the risk ratio (RR).

  • For continuous outcomes, we will use the mean difference between treatment arms.

Unit of analysis issues

Not applicable.

Dealing with missing data

We will not impute missing outcome data for the primary outcome. If data are missing or only imputed data are reported we will contact trial authors to request data on the outcomes only among participants who were assessed.

Assessment of heterogeneity

We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If there is evidence of substantial heterogeneity, we will investigate and report the possible reasons for this.

Assessment of reporting biases

If a sufficient number of studies are identified (e.g. more than 10), we will examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small study effects such as publication bias.

Data synthesis

If sufficient, clinically similar studies are available we will pool their results in meta-analyses using the Cochrane Collaboration's statistical software, Review Manager 2013.

If non-randomised studies have been included, we will use the adjusted results.

For time-to-event data, we will pool HRs using the generic inverse variance facility of Review Manager 2013.

For dichotomous outcomes, we will calculate the RR for each study and these will then be pooled.   

For continuous outcomes, will pool the mean differences (MDs) between the treatment arms at the end of follow-up if all trials measure the outcome on the same scale, otherwise will pool standardised mean differences (SMDs). 

We will use the random-effects models with inverse variance weighting for all meta-analyses (DerSimonian 1986).

Subgroup analysis and investigation of heterogeneity

Since it is expected that only studies with a small number of participants will be available, we do not plan to conduct subgroup analysis.

Sensitivity analysis

We will perform sensitivity analyses excluding studies at high risk of bias.


We thank Jane Hayes, Information Manager, for designing the search strategy and Clare Jess, Managing Editor, for her contribution to the editorial process.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.


Appendix 1. MEDLINE search strategy

1 exp Chondrosarcoma/
2 chondrosarcoma*.mp.
3 exp Chondroma/
4 (enchondroma* or chondroma*).mp.
5 1 or 2 or 3 or 4
6 (intra-lesion* or intralesion*).mp.
7 exp Curettage/
9 (phenol* or ethanol or bone cement).mp.
10 Cryotherapy/
12 6 or 7 or 8 or 9 or 10 or 11
13 surgery.fs.
14 Amputation/
15 (resect* or surgery or amputat*).mp.
16 13 or 14 or 15
17 5 and 12 and 16

[mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

Contributions of authors

  • EFD: Designing search protocol, reviewing articles, collect and analyse data, preparing manuscript

  • PCJ: Designing search protocol, reviewing articles, collect and analyse data, preparing manuscript

  • MS: supervising manuscript, arbiter

Declarations of interest

There are no conflicting interests.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.